: The emergence of immune checkpoint inhibitors (CPIs) has significantly improved outcomes for patients with a variety of malignancies. By blocking the inhibitory signaling pathways of T cells, CPIs are associated with a diverse spectrum of immune-related adverse events (irAEs). Immune-related cutaneous adverse events (ircAE) are the most frequent AE and may result in CPI dose interruption or discontinuation. Current guidelines recommend corticosteroids for the management of irAEs including those affecting skin. Yet ~25% of ircAEs are steroid unresponsive, and their use has revealed a negative effect on survival, underscoring the need for early identification of corticosteroid unresponsiveness and rational therapies. Although the underlying pathogenic mechanism of irAEs remain elusive, autoimmune and autoinflammatory reactions have a putative role in their development and maintenance. Thus, understanding the pathogenic events underlying irAEs are critical to their prevention and treatment. The underlying mechanisms of irAEs remain a significant knowledge gap that we will address in this proposal. Our Central Hypothesis is that patients with ircAEs have unique endotypes associated with polarized immune responses in the skin and blood, which results in corticosteroid responsive and unresponsiveness reactions that may require intervention with targeted immune pathway blockade. In addition, we hypothesize that specific ircAE skin manifestations are associated with unique immune dermatologic responses. Cutaneous irAEs give us a unique opportunity to understand the immune reaction in the involved end organ and systemically. We will test our central hypothesis through; Aim 1: Define and correlate ircAE phenotypes with their immune reaction endotype and response to toxicity- directed therapy. In this aim we hypothesize that ircAEs are associated with distinct, polarized immune endotypes that correlate with specific cutaneous phenotypes and predict response to available interventions (corticosteroids, biologics targeting inflammatory pathways). Aim 2: Identify skin and circulating lipid biomarkers which occur during and after ircAEs. This aim tests the hypothesis that distinct ircAE clinical phenotypes and their endotypes will manifest unique changes in the skin structural and circulatory signaling lipidome and suggest novel therapeutic strategies to mitigate ircAEs. Aim 3: Determine mechanisms associated with corticosteroid unresponsiveness in patients with ircAE. This aim tests the hypothesis that steroid unresponsiveness can be defined by understanding the major mechanistic pathways involved, and ultimately allow targeted therapy to resolve the ircAE. In this translational approach to understanding ircAEs, our goal is to define in patients, the mechanisms involved in ircAEs, activated polarized pathways, and advance our understanding of translational immunology as well as lead to actionable interventions to mitigate these devastating AEs that can limit cancer therapy.